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Ref Type Journal Article
PMID (27988457)
Authors Guffanti F, Chilà R, Bello E, Zucchetti M, Zangarini M, Ceriani L, Ferrari M, Lupi M, Jacquet-Bescond A, Burbridge MF, Pierrat MJ, Damia G
Title In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models.
Journal Neoplasia (New York, N.Y.)
Vol 19
Issue 1
Date 2017 Jan
URL
Abstract Text The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/β (PDGFRα/β) and FGFR1-3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations. In cell assays, lucitanib potently inhibited the growth of tumor cell lines with amplified FGFR1 or mutated/amplified FGFR2. In all xenograft models studied, lucitanib demonstrated marked tumor growth inhibition due to potent inhibition of angiogenesis. Notably, in two lung cancer models with FGFR1 amplification, the antitumor efficacy was higher, suggesting that the simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors can be therapeutically advantageous. Similar antitumor activity was observed in FGFR2 wild-type and amplified or mutated xenograft models. Pharmacokinetic studies showed lucitanib plasma concentrations in the micro/sub-micromolar range demonstrated drug accumulation following repeated lucitanib administration.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Lucitanib Lucitanib 7 5
Drug Name Trade Name Synonyms Drug Classes Drug Description
Lucitanib E-3810|AL3810 DDR1 Inhibitor 8 DDR2 inhibitor 7 FGFR1 Inhibitor 25 FGFR2 Inhibitor 19 PDGFR-alpha Inhibitor 9 VEGFR Inhibitor (Pan) 33 Lucitanib (E-3810) is a multi-tyrosine kinase receptor inhibitor of VEGFR 1-3, DDR2, PDGFRA, and FGFR1-2, that may inhibit tumor angiogenesis, prevent tumor cell proliferation, and induce tumor cell death (PMID: 27988457, PMID: 24696502, PMID: 31619444).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 amp lung carcinoma sensitive Lucitanib Preclinical - Cell line xenograft Actionable in a preclinical study, Lucitanib (E-3810) preferentially inhibited growth of FGFR1-amplified lung carcinoma cell lines in culture and in cell line xenograft models (PMID: 27988457). 27988457